The broad, long term goals of this proposal are to use a novel class of antagonists of the aryl hydrocarbon receptor (AHR), AHR-Protacs, developed herein as 1) a research tool to delineate the mechanisms by which activation of the AHR pathway by environmental agents leads to carcinogenesis in the human population and identify roles of the AHR in other disease processes and 2) a therapeutic agent to treat cancers, diabetes and cardiovascular diseases. Exposures to environmental factors, such as benzo[a]pyrene and 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) are thought to play important roles in the development of human cancers. While these agents are known to exert many of their carcinogenic actions via activation of the AHR, the mechanisms by which the AHR elicits the key events are unknown. Further, it has not yet been established whether targeting the AHR would be an effective chemopreventive approach. Finally, emerging evidence implicates a role for the AHR in not only cancer, but also diabetes and cardiovascular diseases. The immediate goals of the current proposal are to optimize and characterize novel AHR antagonists, some of which have already been developed in our laboratories, as appropriate AHR antagonists. Specific Aims: (1) Synthesis of optimum AHR Protacs. (2) Determine that the optimum AHR Protac molecule(s) inhibits AHR signaling in cultured cells with high efficacy. (3) Determine whether the optimum AHR Protac(s) inhibits the ability of TCDD to alter cell cycle, apoptosis and senescence. (4) Determine whether the optimum AHR Protac(s) alters the AHR pathway with high specificity. The work proposed herein will develop a novel research tool that can be used to identify how inappropriate activation of the AHR by environmental carcinogens leads to human cancers and to understand the role of the AHR in normal biological processes. In addition, this work will set the stage for the development of drugs that target the AHR and may be clinically useful not only as agents that may prevent cancers, but may also be effective in the treatment of diabetes and cardiovascular diseases.